We have discovered trigriluzole (TRLZ), a tripeptide prodrug improved version of the market-drug riluzole (RLZ). The glutamic acid lowering properties of RLZ are ideally suited for the treatment of cocaine (COC) addiction, and TRLZ is a major advance in delivering riluzole in vivo as validated in multiple in vivo studies in mouse, rat, cynomolgous monkey and humans (Phase I PK, safety and tolerability clinical trial). TRLZ is actively transported by the peptide transporter PepT1 prior to peptidase-mediated cleave after absorption. Because of this, TRLZ displays higher oral bioavailability of the active principle RLZ than when RLZ is given alone, a delayed Tmax, longer half-life, less patient-to-patient variability, a greatly reduced or eliminated negative food effect and lack of RLZ first pass-mediated liver function abnormalities. We here seek to discover and validate first-in-class small-molecule treatment to treat cocaine addiction, by first conducting a comprehensive in vivo comparison of both TRLZ and RLZ. Conventional strategies for COC addiction have primarily targeted receptors, transporters and metabolic enzymes and have also included vaccines. However, no strategy, or putative candidate, has led to an approved medication. This therapeutic gap exacerbates societal impacts and costs of COC addiction. For example, COC accounts for 25% of emergency department visits for drug misuse and 13% of admissions to drug abuse treatment programs, and 60-90% of COC addicts relapse after withdrawal. Chronic cocaine exposure dysregulates cellular glutamate uptake and signaling at glutamate excitatory projections onto medium spiny neurons in the nucleus accumbens (NAc), including synaptic strength and intrinsic excitability. We have prepared and evaluated >400 RLZ prodrugs across three generations of structural modifications. The first generation validated our desired in vitro profile, the second established a favorable in vivo profile in multiple species but had hERG activity, and the third contained the positive attributes of the previous two but without hERG activity (IC50 > 30 ?M), leading ultimately to TRLZ. . In Aim 1, we will compare the efficacy and potency of TRLZ and RLZ against relapse to COC seeking in a cue- induced self-administration (SA) model in male and female rats. The route of administration will be i.p followed by p.o. as we anticipate clinical use among COC addicts will conducted using oral dosing, and the once daily dosing of TRLZ is one of its salient benefits, compared to RLZ at twice daily. In Aim 2, we will characterize the effects of TRLZ on the reinforcing and motivational strength of COC in male and female rats maintained under a progressive-ratio (PR) reinforcement schedule. If this program of study yields favorable data for the use of TRLZ in the treatment COC addiction as expected, this is recognized by experts in the field to be sufficient to quality TRLZ to advance into Phase II/III human clinical trials for the treatment of COC addiction, a condition for which there is currently no approved medication. A path for further development has already been identified which involves a combination of private investment and NIDA support for the required clinical trials.